Certain halocarbons, including carbon tetrachloride, halothane, vinyl chloride, 1,1-dichloroethylene, produce sequential disturbances in the function, composition and structure of cytoplasmic organelles of liver parenchymal cells. Carbon tetrachloride and other hepatotoxins, including vinyl chloride, which are highly reactive in free radical reactions, produce similar acute lesions. While it is known that carbon tetrachloride is metabolized, it is not yet understood whether it is injurious because its metabolites catalyze uncontrolled free radical reactions within the cellular membrane or whether specific products of its metabolism act as anti-metabolites. It is proposed to continue to examine the sequential morphologic, enzymatic and compositional changes in cellular membrane systems in cells following poisoning to determine their cause and interrelationships, and to determine the degree to which cellular functions can be preserved or restored, and cell survival prolonged. By comparing the effects of carbon tetrachloride with those of other agents, the presence or absence of common molecular pathways of injury and response of cells to injury will be determined. The basis of action of chemical agents which enhance or protect cells against the toxic action of carbon tetrachloride and other haloalkanes will be examined. Agents which enhance injury will include phenobarbital, ethanol, various insecticides, halogenated biphenyls, and polycyclic hydrocarbons. Protective agents will include antioxidants, glutathione, substituted phenothiazines, steroids, and inhibitors of alcohol dehydrogenase. The proposed researches will provide a clearer understanding of the chemical and morphologic events associated with chemical injury, define the molecular events responsible and how these events can be detected, prevented or reversed in man. BIBLIOGRAPHIC REFERENCES: Moslen, M.T., Reynolds, E.S., Boor, P.J., Bailey, K., and Szabo, S.: Trichloroethylene induced deactivation of cytochrome P-450 and loss of liver glutathione in vivo. Res. Comm. Chem. Path. Pharmacol. 16, 109, 1977. Reynolds, E.S., Moslen, M. T., Boor, P.J., Bailey, K., and Szabo, S.: Trichloroethylene induced deactivation of liver endoplasmic reticulum and glutathione depletion. Abstracts of Papers, Society of Toxicology, Sixteenth Annual Meeting, 1977.